Decreased Oral Absorption of Cyclosporine A after Liver Ischemia-Reperfusion Injury in Rats: The Contribution of CYP3A and P-Glycoprotein to the First-Pass Metabolism in Intestinal Epithelial Cells

Ikemura, Kenji; Urano, Kimihiko; Matsuda, Hiroko; Mizutani, Hideki; Iwamoto, Takuya; Okuda, Masahiro

doi:10.1124/jpet.108.145581

Cited by 34 publications

(24 citation statements)

References 33 publications

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“…Our previous studies demonstrated that the expression levels of P-gp in the upper, middle, and lower small intestine were significantly increased after liver I/R (Ikemura et al, 2009(Ikemura et al, , 2012. Therefore, we first evaluated the mRNA expression levels of the two distinct genes encoding the rat P-gp, Mdr1a (Abcb1a) and Mdr1b (Abcb1b), in the small intestine of Sham and I/R rats.…”

Section: Resultsmentioning

confidence: 99%

“…Liver I/R model rats were prepared according to our previous report (Ikemura et al, 2009). Briefly, after the rats were anesthetized by intraperitoneal injection of 50 mg/kg pentobarbital, partial hepatic ischemia was achieved by clamping the blood vessels of the left portal vein and hepatic artery using a microvessel clip.…”

Section: Methodsmentioning

confidence: 99%

“…It is known that there are marked interindividual variations in the expression and function of P-gp (Masuda and Inui, 2006). In our previous study, we used rats after liver ischemia-reperfusion (I/R) injury as a model for the conditions within a graft liver immediately after liver transplantation, showing that the expression levels of P-gp in the small intestine were elevated after liver I/R (Ikemura et al, 2009). However, the mechanism for the elevated P-gp in the small intestine after liver I/R remained to be clarified.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-145 Post-transcriptionally Regulates the Expression and Function of P-glycoprotein in Intestinal Epithelial Cells

et al. 2012

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P-glycoprotein (P-gp/MDR1) is a multispecific efflux transporter regulating the pharmacokinetics of various drugs. Although P-gp expression in the small intestine is elevated after liver ischemiareperfusion (I/R) injury, the regulatory mechanism remains to be clarified. MicroRNAs (miRNAs) play an important role in the posttranscriptional regulation of the expression of drug transporters. Here, we investigated the intestinal expression profile of miRNAs after liver I/R and the role of miRNAs in the post-transcriptional regulation of P-gp in intestinal epithelial cells. Microarray analysis showed that microRNA-145 (miR-145) level was decreased in the small intestine of I/R rats. This downregulation of miR-145 was further confirmed by real-time polymerase chain reaction. In silico analysis revealed that 39-untranslated regions (UTRs) of rat Mdr1a, mouse Mdr1a, and human MDR1 mRNA retain binding sites for miR-145. Luciferase assays using MDR1 39-UTR reporter plasmid in HEK293 cells showed that luciferase activity was decreased by the overexpression of miR-145, and the deletion of miR-145 binding site within MDR1 39-UTR abolished this decreased luciferase activity. The downregulation of miR-145 in Caco-2 cells, an epithelial cell line derived from human colon, increased P-gp expression and efflux activity of rhodamine 123, but not MDR1 mRNA level. These findings demonstrated that miR-145 negatively regulates the expression and function of P-gp through the repression of mRNA by direct interaction on the 39-UTR of MDR1 mRNA. In addition, the downregulation of miR-145 should significantly contribute to the elevated intestinal P-gp expression after liver I/R. Our results provide new insight into the post-transcriptional regulation of intestinal P-gp.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MicroRNA-145 Post-transcriptionally Regulates the Expression and Function of P-glycoprotein in Intestinal Epithelial Cells

et al. 2012

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“…Therefore, it is likely that the expression and function of these transporters are altered after the liver IR injury. Indeed, the limited data available in the literature (7)(8)(9)(10) suggest that the mRNA and protein levels of the canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) may be altered by warm hepatic IR injury. However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers

2012

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-Purpose.A few studies have shown that normothermic hepatic ischemia-reperfusion (IR) injury may affect the mRNA and/or protein levels of canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2). However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown. Therefore, the purpose of this study was to investigate the effects of warm hepatic IR on the hepatobiliary disposition of rhodamine 123 (RH-123), a P-gp substrate, and its glucuronidated metabolite (RH-Glu), an Mrp2 substrate, in rats. Methods. Twenty four or 72 h following a 60-min partial ischemia or sham operation in rats, livers were isolated and perfused ex vivo with a constant concentration (~100 ng/mL) of RH-123. The concentration of RH-123 and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were determined in the outlet perfusate, bile, and the liver tissue using HPLC, and relevant pharmacokinetic parameters were estimated. Results. Twentyfour-h IR caused a significant reduction in the hepatic extraction ratio of RH-123 (IR: 0.857 ± 0.078; Sham: 0.980 ± 0.017) and the biliary recovery of the parent drug and RH-Glu by 43% and 44%, respectively. The reductions in the biliary recovery were associated with significant reductions in the apparent biliary clearance of RH-123 and RH-Glu. Mass balance data showed that the formation of the glucuronidated or deacylated metabolite was not significantly affected by the 24-h IR injury. In contrast to the 24-h IR, the injury did not have any effect on the hepatobiliary disposition of RH-123 or its metabolites following 72 h of reperfusion. Conclusions. It is concluded that the pharmacokinetics of drugs that are subject to biliary excretion by the canalicular P-gp and Mrp2 transporters may be altered shortly after hepatic IR injury.

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“…18,29) Furthermore, radixin has been just recently proposed to play a crucial role in regulating the membrane localization and functional activity of P-gp in the small intestinal by using mice lacking radixin. 32) Since the small intestinal P-gp acts as a first barrier against the absorption of various substrate drugs administered via the oral route, [33][34][35][36][37][38] it seems to be important to accumulate the evidence with regard to the regulatory factors for the plasma membrane localization of P-gp. However, there has been no direct evidence investigating the molecular interaction between P-gp and radixin in the small intestine and the role of radixin in the alteration mechanism of P-gp.…”

mentioning

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Radixin Influences the Changes in the Small Intestinal P-Glycoprotein by Etoposide Treatment

Kobori

Harada

Nakamoto

et al. 2013

Biological & Pharmaceutical Bulletin

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Previously, we reported that repeated oral administration of etoposide (ETP) increases P-glycoprotein (P-gp) expression in association with activation of ezrin/radixin/moesin (ERM) in the small intestine. Radixin has recently attracted attention for its critical role in the plasma membrane localization of certain drug transporters including P-gp by working as a scaffold protein. However, there have been no report investigating that radixin really interacts with small intestinal P-gp and is involved in the mechanism by which the levels of P-gp are altered. Here, we examined whether radixin is involved in the increased P-gp expression in the small intestine after ETP treatment. Repeated oral treatment with ETP (10 mg/kg/day) for 7 d significantly increased ERM proteins bound to P-gp in the small intestine as determined by immunoprecipitation analysis. In particular, radixin but not ezrin or moesin bound to P-gp was dramatically increased in association with the up-regulation of P-gp in the small intestinal membrane, and radixin was highly colocalized with P-gp as measured by immunofluorescence analysis. In conclusion, radixin may contribute, at least in part, to an increase in the expression of the small intestinal P-gp upon induction with repeated oral treatment with ETP.Key words P-glycoprotein; radixin; small intestine; ATP-binding cassette transporterThe expression levels and functional activity of plasma membrane proteins are not necessarily dependent upon their mRNA levels, as exemplified by P-glycoprotein (P-gp). 1,2)While various transcriptional factors have been identified as key regulators of P-gp mRNA levels, 3) little is known about the post-transcriptional regulation of this protein.We have focused our previous studies on ezrin, radixin and moesin, all of which are involved to some degree in the post-transcriptional regulation of P-gp. 4) Ezrin was originally identified as a component of microvilli from chicken intestinal brush borders. 5) Radixin was isolated from rat liver as a component of the adherens junctions, 6) while moesin was characterized as a heparin-binding protein from smooth muscle cells in the bovine uterus. 7,8) These three proteins are closely related with ∼75% amino-acid sequence homology, and together they comprise the ezrin, radixin and moesin (ERM) family.9) The high sequence homology of these proteins makes them difficult to distinguish from each other unless specific antibodies against each individual ERM member are used. Thus, ezrin, radixin and moesin have been considered as the ERM family as a whole in the majority of previous reports. The ERM play several critical roles in tissue morphology and organization as well as in cell motility, 5,[10][11][12][13][14] by acting alone as a cross linker between the plasma membrane and the actin cytoskeleton. 5,15,16) Recently, ERM have attracted much attention as scaffold proteins regulating the plasma membrane localization and functional activities of several drug transporters including P-gp. 4,15,17,18) In fact, ERM have already been...

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Decreased Oral Absorption of Cyclosporine A after Liver Ischemia-Reperfusion Injury in Rats: The Contribution of CYP3A and P-Glycoprotein to the First-Pass Metabolism in Intestinal Epithelial Cells

Cited by 34 publications

References 33 publications

MicroRNA-145 Post-transcriptionally Regulates the Expression and Function of P-glycoprotein in Intestinal Epithelial Cells

MicroRNA-145 Post-transcriptionally Regulates the Expression and Function of P-glycoprotein in Intestinal Epithelial Cells

Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers

Radixin Influences the Changes in the Small Intestinal P-Glycoprotein by Etoposide Treatment

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